Histone demethylase UTX mediates removal of repressive trimethylation of histone H3 lysine 27 (H3K27me3) to establish a mechanistic switch to activate large sets of genes. Mutation of Utx has recently been shown to be associated with Kabuki syndrome, a rare congenital anomaly syndrome with dementia. However, its biological function in the brain is largely unknown. Here, we observe that deletion of Utx results in increased anxiety-like behaviors and impaired spatial learning and memory in mice. Loss of Utx in the hippocampus leads to reduced long-term potentiation and amplitude of miniature excitatory postsynaptic current, aberrant dendrite development and defective synapse formation. Transcriptional profiling reveals that Utx regulates a subset of genes that are involved in the regulation of dendritic morphology, synaptic transmission, and cognition. Specifically, Utx deletion disrupts expression of neurotransmitter 5-hydroxytryptamine receptor 5B (Htr5b). Restoration of Htr5b expression in newborn hippocampal neurons rescues the defects of neuronal morphology by Utx ablation. Therefore, we provide evidence that Utx plays a critical role in modulating synaptic transmission and cognitive behaviors. Utx cKO mouse models like ours provide a valuable means to study the underlying mechanisms of the etiology of Kabuki syndrome.
During lactation, female small mammals frequently reduce their fat reserves to very low levels. The function of this reduction is unclear, as calculations suggest that the contribution of the withdrawn energy from fat to the total energy balance of lactation is trivial. An alternative hypothesis is that reducing fat leads to a reduction in circulating adipokines, such as leptin, that play a role in stimulating the hyperphagia of lactation. We investigated the role of circulating leptin in lactation by repleting leptin levels using miniosmotic pumps during the last 7 days of lactation in Brandt's voles (Lasiopodomys brandtii), a model small wild mammal we have extensively studied in the context of lactation energy demands. Repletion of leptin resulted in a dose-dependent reduction of body mass and food intake in lactating voles. Comparisons to nonreproducing individuals suggests that the reduced leptin in lactation, due to reduced fat stores, may account for ϳ16% of the lactational hyperphagia. Reduced leptin in lactation may, in part, cause lactational hyperphagia via stimulatory effects on hypothalamic orexigenic neuropeptides (neuropeptide Y and agouti-related peptide) and inhibition of the anorexigenic neuropeptide (proopiomelanocortin). These effects were reversed by the experimental repletion of leptin. There was no significant effect of leptin treatment on daily energy expenditure, milk production or pup growth, but leptin repletion did result in a reversal of the suppression of uncoupling protein-1 levels in brown adipose tissue, indicating an additional role for reducing body fat and leptin during peak lacation. sustained energy intake; neuropeptide Y, agouti-related peptide, proopiomelanocortin, uncoupling protein-1 LACTATION IS WIDELY AGREED to be the most energetically demanding phase of the mammalian female life cycle (53, 65), particularly in small mammals. For example, over a period of ϳ18 days, the lactating female mouse (Mus musculus) increases her food intake by a factor of five (29,33). At the same time, she remodels her morphology, growing the length of the alimentary tract by ϳ20% (ϳ12 cm), doubling the size of the liver, and growing other internal organs like the pancreas. This is not just a generalized increase in size, because the lactating female also withdraws calcium from the major bones and almost all the lipids from her white adipose tissue (WAT) (25,30,36,49,68). Simultaneous to the behavioral and morphological changes, the female mouse also undergoes a radical alteration in her physiology. This includes increasing the capacity of the mammary glands to synthesize and secrete milk, combined with a profound reduction of the levels of uncoupling proteins-1 (UCP-1) and UCP-3 in brown adipose tissue (BAT) (55,75,87). The elevated food intake is closely coordinated with milk production and varies tremendously across individuals (37,41,86). Similar patterns of elevated intake and morphological/physiological changes in lactation are observed in many other species of small mammals (28,45,49,5...
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